Near‐Infrared Thermally Activated Delayed Fluorescence Nanoparticle: A Metal‐Free Photosensitizer for Two‐Photon‐Activated Photodynamic Therapy at the Cell and Small Animal Levels

Abstract Thermally activated delayed fluorescence (TADF) materials with extremely small singlet‐triplet energy offsets have opened new horizons for the development of metal‐free photosensitizers for photodynamic therapy (PDT) in recent years. However, the exploration of near‐infrared (NIR) TADF emitters for efficient two‐photon‐excited (TPE) PDT is still a formidable challenge, thus it has not been reported yet. In this study, purely organic photosensitizers (PSs) based on the TADF nanoparticles (NIR‐TADF NPs) are designed for efficient TPE‐PDT, which show excellent singlet oxygen generation ability. Thanks to the intrinsic two‐photon excitation and NIR emission characteristics, the NIR‐TADF NPs demonstrate promising potential in both single‐photon‐excited (SPE) and TPE NIR imaging. More importantly, the anti‐tumor efficiency and biosafety of TADF‐based PSs at the small animal level are confirmed in A549 tumor xenograft models under TPE laser irradiance, which will facilitate the practical biomedical applications of TADF materials. This work not only provides a promising strategy to develop metal‐free PSs, but also expands the applied scope of TADF‐based nanotherapeutics and advances their possible clinical translation in cancer therapy.